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Sildenafil ameliorates cognitive deficits and tau pathology in a senescence-accelerated mouse model


Year of Publication:
Contact PI Name:
Norberto Aguirre
Contact PI Affiliation:
Department of Pharmacology, University of Navarra, School of Pharmacy, Pamplona, Spain
Lourdes Orejana, Lucía Barros-Miñones, Joaquín Jordán, Elena Puerta
Primary Reference (PubMED ID):
Funding Source:
Spanish Ministry of Science and Innovation
Study Goal and Principal Findings:

The aim of this study was to explore whether sildenafil could reverse the memory impairments shown by SAMP8 mice as well as the underlying mechanisms.Sildenafil administration (7.5 mg/kg for 4 weeks) to 5-month-old SAMP8 mice attenuated spatial learning and memory impairments shown by these mice in the Morris Water Maze. Tau hyperphosphorylation (AT8 but not PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of sildenafil-treated mice, an effect probably related to a decrease in cyclin-dependent kinase 5 protein expression and activity (p25/p35 ratio). Sildenafil treatment was associated with phosphosphorylated Akt, which was associated with an increase of glycogen synthase kinase-3 phosphorylation, providing a plausible explanation for the reductions in tau hyperphosphorylation  and attenuation of cognitive deficits shown by 9-month-old SAMP8 mice. Overall, sildenafil might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Phosphodiesterase Type 5A (PDE5A)

Animal Model

Model Information:
Model Type:
Accelerated Aging
Strain/Genetic Background:
AKR/Jx suspected outbreeding to unknown line

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Cyclin-Dependent Kinase 5 (CDK5)
GSK3 beta/phospho-GSK3 beta
phospho-Protein Kinase B (phospho-Akt/PKB)